U.S. patent application number 10/591895 was filed with the patent office on 2008-10-30 for pyrrolopyridine-2-carboxylic acid hydrazides.
Invention is credited to Stuart Edward Bradley, Revathy Perpetua Jeevaratnam, Thomas Martin Krulle, Martin James Procter, Robert John Rowley, Gerard Hugh Thomas, Ana Valdes.
Application Number | 20080269277 10/591895 |
Document ID | / |
Family ID | 34919586 |
Filed Date | 2008-10-30 |
United States Patent
Application |
20080269277 |
Kind Code |
A1 |
Bradley; Stuart Edward ; et
al. |
October 30, 2008 |
Pyrrolopyridine-2-Carboxylic Acid Hydrazides
Abstract
Compounds of Formula (I) or pharmaceutically acceptable salts
thereof, are inhibitors of glycogen phosphorylase and are useful in
the prophylactic or therapeutic treatment of diabetes,
hyperglycemia, hypercholesterolemia, hyperinsulinemia,
hyperlipidemia, hypertension, atherosclerosis or tissue ischemia
e.g. myocardial ischemia, or as cardioprotectants or inhibitors of
abnormal cell growth. ##STR00001##
Inventors: |
Bradley; Stuart Edward;
(Oxford, GB) ; Jeevaratnam; Revathy Perpetua;
(Oxford, GB) ; Krulle; Thomas Martin; (Oxford,
GB) ; Procter; Martin James; (Oxford, GB) ;
Rowley; Robert John; (Oxford, GB) ; Thomas; Gerard
Hugh; (Oxford, GB) ; Valdes; Ana; (Oxford,
GB) |
Correspondence
Address: |
OSI PHARMACEUTICALS, INC.
41 PINELAWN ROAD
MELVILLE
NY
11747
US
|
Family ID: |
34919586 |
Appl. No.: |
10/591895 |
Filed: |
March 8, 2005 |
PCT Filed: |
March 8, 2005 |
PCT NO: |
PCT/GB05/00885 |
371 Date: |
November 5, 2007 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60551254 |
Mar 8, 2004 |
|
|
|
Current U.S.
Class: |
514/300 ;
546/113 |
Current CPC
Class: |
A61P 3/10 20180101; A61P
9/00 20180101; A61P 35/00 20180101; A61P 9/10 20180101; C07D 471/04
20130101; A61P 3/00 20180101; A61P 9/12 20180101; A61P 3/06
20180101 |
Class at
Publication: |
514/300 ;
546/113 |
International
Class: |
A61K 31/437 20060101
A61K031/437; C07D 471/04 20060101 C07D471/04; A61P 3/10 20060101
A61P003/10; A61P 3/06 20060101 A61P003/06; A61P 9/12 20060101
A61P009/12 |
Claims
1. A compound of formula (I): ##STR00049## or a pharmaceutically
acceptable salt thereof, wherein: one of X.sub.1, X.sub.2, X.sub.3
and X.sub.4 is N and the others are C; Y is --C(O)--,
--S(O).sub.2--, or --C(NH)--; Z is C.sub.1-4alkylene, oxygen,
--(CH.sub.2).sub.mO--, --O(CH.sub.2).sub.m--, --NR--,
--(CH.sub.2).sub.mNR--, --NR(CH.sub.2).sub.m--,
--(CH.sub.2).sub.mS(O).sub.2-- or a bond; m is 1, 2, 3, or 4; R is
C.sub.0-4alkyl, C.sub.0-4alkylaryl, or C.sub.0-4alkylhetaryl;
R.sup.1 and R.sup.1' are each independently, halogen, hydroxy,
cyano, C.sub.0-4alkyl, C.sub.1-4alkoxy, fluoromethyl,
difluoromethyl, trifluoromethyl, ethenyl, or ethynyl; R.sup.2 is
C.sub.0-4alkyl, COOR.sup.6, COR.sup.6,
C.sub.1-4alkoxyC.sub.1-4alkyl-, hydroxyC.sub.1-4alkyl-,
cycloalkylC.sub.0-4alkyl-, arylC.sub.0-4alkyl-, or
hetarylC.sub.0-4alkyl-, wherein any of the aryl or hetaryl rings
are optionally substituted with 1-2 independent halogen, cyano,
C.sub.1-4alkyl, C.sub.1-4alkoxy,
--N(C.sub.0-4alkyl)(C.sub.0-4alkyl), --SO.sub.2C.sub.1-4alkyl,
--SO.sub.2N(C.sub.0-4alkyl)(C.sub.0-4alkyl), hydroxy, fluoromethyl,
difluoromethyl, or trifluoromethyl substituents; R.sup.3 is
hydrogen, --COOC.sub.0-4alkyl, C.sub.1-4alkoxy, C.sub.1-4alkyl,
arylC.sub.1-4alkylthio-, --C.sub.0-4alkylaryl,
--C.sub.0-4alkylhetaryl, --C.sub.0-4alkylcycloalkyl, or
--C.sub.0-4alkylheterocyclyl, wherein any of the rings is
optionally substituted with 1-3 independent halogen, cyano,
C.sub.1-4alkyl, fluoromethyl, difluoromethyl, trifluoromethyl,
--C.sub.0-4alkylNHC(O)O(C.sub.1-4alkyl),
--C.sub.0-4alkylNR.sup.7R.sup.8, C(O)R.sup.9,
C.sub.1-4alkoxyC.sub.0-4alkyl-, --COOC.sub.0-4alkyl,
--C.sub.0-4alkylNHC(O)R.sup.9,
--C.sub.0-4alkylC(O)N(R.sup.10).sub.2,
--C.sub.1-4alkoxyC.sub.1-4alkoxy, hydroxyC.sub.0-4alkyl-,
--NHSO.sub.2R.sup.10, --SO.sub.2(C.sub.1-4alkyl),
--SO.sub.2NR.sup.11R.sup.12, 5- to 6-membered heterocyclyl,
phenylC.sub.0-2alkoxy, or phenylC.sub.0-2alkyl substituents,
wherein phenyl is optionally substituted with 1-2 independent
halogen, cyano, C.sub.1-4alkyl, C.sub.1-4alkoxy,
--N(C.sub.0-4alkyl)(C.sub.0-4alkyl), --SO.sub.2C.sub.1-4alkyl,
--SO.sub.2N(C.sub.0-4alkyl)(C.sub.0-4alkyl), hydroxy, fluoromethyl,
difluoromethyl, or trifluoromethyl substituents, or two bonds on a
ring carbon of the heterocyclyl group optionally can form an oxo
(.dbd.O) substituent; or R.sup.3 is
--NR.sup.4(--C.sub.0-4alkylR.sup.5); R.sup.4 is C.sub.0-3alkyl,
--C.sub.2-3alkyl-NR.sup.7R.sup.8, C.sub.3-6cycloalkyl optionally
substituted by hydroxyC.sub.0-4alkyl- further optionally
substituted by hydroxy, C.sub.1-2alkoxyC.sub.2-4alkyl-, or
C.sub.1-2alkyl-S(O).sub.n--C.sub.2-3alkyl-; n is 0, 1, or 2;
R.sup.5 is hydrogen, hydroxyC.sub.2-3alkyl-,
C.sub.1-2alkoxyC.sub.0-4alkyl, or aryl, hetaryl, or heterocycle;
wherein a heterocyclic nitrogen-containing R.sup.5 ring optionally
is mono-substituted on the ring nitrogen with C.sub.1-4alkyl,
benzyl, benzoyl, C.sub.1-4alkyl-C(O), --SO.sub.2C.sub.1-4alkyl,
--SO.sub.2N(C.sub.0-4alkyl)(C.sub.0-4alkyl),
C.sub.1-4alkoxycarbonyl, or aryl(C.sub.1-4alkoxy)carbonyl; and
wherein the R.sup.5 rings are optionally mono-substituted on a ring
carbon with halogen, cyano, C.sub.1-4alkyl-C(O),
C.sub.1-4alkyl-SO.sub.2--, C.sub.1-4alkyl, C.sub.1-4alkoxy,
hydroxy, --N(C.sub.0-4alkyl)(C.sub.0-4alkyl),
hydroxyC.sub.0-4alkyl-, or C.sub.0-4alkylcarbamoyl-, provided that
no quaternised nitrogen is included; or two bonds on a ring carbon
of the heterocyclyl group optionally can form an oxo (.dbd.O)
substituent; R.sup.6 is C.sub.1-4alkyl, aryl or hetaryl; R.sup.7
and R.sup.8 are independently C.sub.0-4alkyl, C.sub.3-6cycloalkyl
or CO(C.sub.1-4alkyl); R.sup.9 is C.sub.1-4alkyl or
C.sub.3-6cycloalkyl; R.sup.10 is C.sub.0-4alkyl or
C.sub.3-6cycloalkyl; and R.sup.11 and R.sup.12 are independently
C.sub.0-4alkyl or together with the nitrogen to which they are
attached may form a 4- to 6-membered heterocycle; provided there
are no nitrogen-oxygen, nitrogen-nitrogen, oxygen-oxygen or
nitrogen-halogen bonds in the grouping --Y-Z-R.sup.3.
2. A compound according to claim 1, or a pharmaceutically
acceptable salt thereof, wherein X.sub.3 is N.
3. A compound according to claim 1, or a pharmaceutically
acceptable salt thereof, wherein X.sub.1 is N.
4-15. (canceled)
16. A compound of formula (IV): ##STR00050## wherein R.sup.1,
R.sup.1', R.sup.2, X.sub.1, X.sub.2, X.sub.3 and X.sub.4 are as
defined in claim 1, or a protected derivative thereof.
17. A compound according to claim 1, or a pharmaceutically
acceptable salt thereof, wherein Y is --C(O)-- or
--S(O).sub.2--.
18. A compound according to claim 1, or a pharmaceutically
acceptable salt thereof, wherein Z is C.sub.1-4alkylene, oxygen,
--(CH.sub.2).sub.mO--, --NR-- or a bond.
19. A compound according to claim 1, or a pharmaceutically
acceptable salt thereof, wherein R.sup.1 and R.sup.1' are each
independently, hydrogen or halogen.
20. A compound according to claim 19, or a pharmaceutically
acceptable salt thereof, wherein one of R.sup.1 and R.sup.1' is
hydrogen and the other is 5-chloro.
21. A compound according to claim 1, or a pharmaceutically
acceptable salt thereof, wherein R.sup.2 is hydrogen.
22. A compound according to claim 1, or a pharmaceutically
acceptable salt thereof, wherein R.sup.3 is hydrogen,
--NR.sup.4R.sup.5, --NR.sup.4(C.sub.1-4alkylR.sup.5), aryl,
hetaryl, or heterocyclyl wherein any of the rings is optionally
substituted as defined in claim 1.
23. A compound selected from: ##STR00051## ##STR00052##
##STR00053## or a pharmaceutically acceptable salt thereof.
24. A compound represented by ##STR00054## or a pharmaceutically
acceptable salt thereof.
25. A pharmaceutical composition comprising a compound according to
claim 1, or a pharmaceutically acceptable salt thereof; and a
pharmaceutically acceptable carrier.
26. A method for the treatment of a disease or condition in which
glycogen phosphorylase plays a role comprising a step of
administering to a subject in need thereof an effective amount of a
compound according to claim 1, or a pharmaceutically acceptable
salt thereof.
27. A method for the treatment of hyperglycemia or diabetes
comprising a step of administering to a subject in need thereof an
effective amount of a compound according to claim 1, or a
pharmaceutically acceptable salt thereof.
28. A method for the prevention of diabetes in a human
demonstrating pre-diabetic hyperglycemia or impaired glucose
tolerance comprising a step of administering to a subject in need
thereof an effective prophylactic amount of a compound according to
claim 1, or a pharmaceutically acceptable salt thereof.
29. A method for the treatment of hypercholesterolemia,
hyperinsulinemia, hyperlipidemia, hypertension, atherosclerosis or
tissue ischemia, or achieving cardioprotection or inhibition of
abnormal cell growth, comprising a step of administering to a
subject in need thereof an effective amount of a compound according
to claim 1, or a pharmaceutically acceptable salt thereof.
30. A compound of formula (IV): ##STR00055## wherein R.sup.1,
R.sup.1', R.sup.2, X.sub.1, X.sub.2, X.sub.3 and X.sub.4 are as
defined in claim 1, or a protected derivative thereof.
Description
BACKGROUND OF THE INVENTION
[0001] The present invention is directed to
pyrrolopyridine-2-carboxylic acid hydrazides. In particular, the
present invention is directed to pyrrolopyridine-2-carboxylic acid
hydrazides that are inhibitors of glycogen phosphorylase.
[0002] Insulin dependent Type I diabetes and non-insulin dependent
Type II diabetes continue to present treatment difficulties even
though clinically accepted regimens that include diet, exercise,
hypoglycemic agents, and insulin are available. Treatment is
patient dependent therefore there is a continuing need for novel
hypoglycemic agents, particularly ones that may be better tolerated
with fewer adverse effects.
[0003] The liver and certain other organs produce glucose (thereby
raising the blood sugar level) by breaking down glycogen or by
synthesizing glucose from small molecule precursors. The breakdown
of glycogen is catalyzed by glycogen phosphorylase enzyme.
Accordingly, inhibiting glycogen phosphorylase ("GP") may lower the
elevated blood sugar level in diabetic patients.
[0004] Similarly, hypertension and its associated pathologies such
as, for example, atherosclerosis, lipidemia, hyperlipidemia and
hypercholesterolemia have been associated with elevated insulin
levels (hyperinsulinemia), which can lead to abnormal blood sugar
levels. Furthermore, myocardial ischemia can result. Such maladies
may be treated with hypoglycemic agents, including compounds that
inhibit glycogen phosphorylase. Accordingly, it is accepted that
compounds that inhibit glycogen phosphorylase (see, for example,
U.S. Pat. No. 6,297,269) are useful in the treatment of diabetes,
hyperglycemia, hypercholesterolemia, hyperinsulinemia,
hyperlipidemia, atherosclerosis or myocardial ischemia.
Nevertheless, it would be desirable to obtain other novel compounds
that inhibit glycogen phosphorylase.
[0005] R. Kurukulasuriya, J. T. Link, et al., Current Medicinal
Chem., 10:99-121 (2003) describes "Prospects for Pharmacologic
Inhibition of Hepatic Glucose Production." R. Kurukulasuriya, J. T.
Link, et al., Current Medicinal Chem., 10: 123-153 (2003) describes
"Potential Drug Targets and Progress Towards Pharmacologic
Inhibition of Hepatic Glucose Production."
[0006] U.S. Pat. No. 6,297,269 and European Patent No. EP 0832066
describes substituted N-(indole-2-carbonyl)amides and derivatives
as glycogen phosphorylase inhibitors. U.S. Pat. Nos. 6,107,329 and
6,277,877 describe substituted N-(indole-2-carbonyl)glycinamides
and derivatives as glycogen phosphorylase inhibitors. U.S. Pat. No.
6,399,601 describes bicyclic pyrrolyl amides as glycogen
phosphorylase inhibitors. International Patent Publication No. WO
03/037864 describes indole derivatives as glycogen phosphorylase
inhibitors. European Patent Application Nos. EP 0978276 and EP
1136071 describe inhibitors of human glycogen phosphorylase and
their use. International Patent Publication No. WO 01/68055
describes glycogen phosphorylase inhibitors. U.S. Pat. No.
5,952,322 describes a method of reducing non-cardiac ischemial
tissue damage using glycogen phosphorylase inhibitors.
[0007] European Patent Application No. EP 1177791 describes the use
of glycogen phosphorylase inhibitors to inhibit abnormal cell
growth, e.g. in the treatment of cancer and hyperproliferative
disorders.
[0008] International Patent Publication No. WO 04/104001 (published
after the priority date of the present application) discloses
pyrrolopyridine-2-carboxylic acid amide inhibitors of glycogen
phosphorylase.
[0009] International Patent Publication No. WO 04/113345 (published
after the priority date of the present application) discloses fused
pyrrole compounds as inhibitors of glycogen phosphorylase.
[0010] International Patent Publication No. WO 01/55146 describes
arylamidines. International Patent Publication No. WO 01/62775
describes antiarrhythmic peptides. International Patent Publication
No. WO 01/96346 describes tricyclic compounds. International Patent
Publication No. WO 02/16314 describes substituted polyamine
compounds. International Patent Publication No. WO 02/20475
describes serine protease activity inhibitors. International Patent
Publication No. WO 02/40469 describes bombesin receptor
antagonists. International Patent Publication No. WO 02/46159
describes guanidine and amidine derivatives. International Patent
Publication No. WO 00/69815 describes ureido-substituted cyclic
amine derivatives.
[0011] International Patent Publication No. WO 00/43384 describes
aromatic heterocyclic compounds. International Patent Publication
Nos. WO 02/26697 and WO 00/76970 describe aromatic derivatives.
International Patent Publication No. WO 01/32622 describes indoles.
European Patent Application No. EP 1101759 describes phenylazole
compounds. European Patent Application No. EP 1179341 describes
cyclic amino compounds. U.S. Pat. No. 6,037,325 describes
substituted heterocyclic compounds. U.S. Pat. No. 5,672,582
describes 4-substituted cyclohexylamine derivatives. European
Patent Application No. EP 1201239 describes cyclic amine CCR3
antagonists. International Patent Publication No. WO 98/25617
describes substituted arylpiperazines. U.S. Pat. No. 5,756,810
describes preparing 3-nitro benzoate compounds.
[0012] U.S. Pat. No. 5,710,153 describes tetrazole compounds. U.S.
Pat. Nos. 6,174,887 and 6,420,561 describe amide compounds. S. P.
Hiremath et al., Acta Ciencia Indica, XVIII:397 (1992) describes
the synthesis and biological activities of
indolylthiosemicarbazides and semicarbazides. International Patent
Publication No. WO 96/36595 describes 3,4-disubstituted
phenylsulfonamides. U.S. Pat. No. 5,618,825 describes combinatorial
sulfonamide libraries. European Patent Application No. EP 0810221
describes oxygen-containing heterocyclic derivatives. European
Patent Application No. 0345990 describes polypeptide compounds.
European Patent Application No. 0254545 describes diamine
compounds.
[0013] International Patent Publication No. WO 97/31016 describes
inhibitors of SH2-mediated processes. U.S. Pat. No. 6,034,067
describes serine protease inhibitors. International Patent
Publication No. WO 97/17985 and U.S. Pat. No. 6,107,309 describe
hemoregulatory compounds. U.S. Pat. No. 6,432,921 describes
thrombin inhibitors. U.K. Patent Application No. GB 2292149
describes peptide inhibitors of pro-interleukin-1.beta. converting
enzyme. U.S. Pat. No. 5,821,241 describes fibrinogen receptor
antagonists.
[0014] International Patent Publication No. WO 01/02424 describes
peptide boronic acid compounds. U.S. Pat. Nos. 6,001,811, 5,869,455
and 5,618,792 describe oxadiazole, thiadiazole and triazole
peptoids. U.S. Pat. Nos. 5,885,967, 6,090,787 and 6,124,277
describe thrombin inhibiting peptide derivatives. U.S. Pat. No.
6,455,529 describes adhesion receptor antagonists. U.S. Pat. No.
6,410,684 describes serine protease inhibitors.
[0015] International Patent Publication No. WO 01/94310 describes
bis-heterocyclic alkaloids. U.S. Patent Publication No.
20030004162A1, European Patent Application No. EP 0846464 and
International Patent Publication No. WO 96/39384 describe glycogen
phosphorylase inhibitors. International Patent Publication No. WO
97/28798 describes pyrrolidine derivatives. U.S. Pat. No. 5,346,907
describes amino acid analogs.
SUMMARY OF THE INVENTION
[0016] Compounds of formula (I):
##STR00002##
or pharmaceutically acceptable salts thereof, are inhibitors of
glycogen phosphorylase and are useful in the prophylactic or
therapeutic treatment of diabetes, hyperglycemia,
hypercholesterolemia, hyperinsulinemia, hyperlipidemia,
hypertension, atherosclerosis or tissue ischemia e.g. myocardial
ischemia, or as cardioprotectants or inhibitors of abnormal cell
growth.
DETAILED DESCRIPTION OF THE INVENTION
[0017] The present invention is directed to a compound of formula
(I):
##STR00003##
or a pharmaceutically acceptable salt thereof, wherein:
[0018] one of X.sub.1, X.sub.2, X.sub.3 and X.sub.4 is N and the
others are C;
[0019] Y is --C(O)--, --S(O).sub.2--, or --C(NH)--;
[0020] Z is C.sub.1-4alkylene, oxygen, --(CH.sub.2).sub.mO--,
--O(CH.sub.2).sub.m--, --NR--, --(CH.sub.2).sub.mNR--,
--NR(CH.sub.2).sub.m--, --(CH.sub.2).sub.mS(O).sub.2--, or a
bond;
[0021] m is 1, 2, 3, or 4;
[0022] R is C.sub.0-4alkyl, C.sub.0-4alkylaryl, or
C.sub.0-4alkylhetaryl;
[0023] R.sup.1 and R.sup.1' are each independently, halogen,
hydroxy, cyano, C.sub.0-4alkyl, C.sub.1-4alkoxy, fluoromethyl,
difluoromethyl, trifluoromethyl, ethenyl, or ethynyl;
[0024] R.sup.2 is C.sub.0-4alkyl, COOR.sup.6, COR.sup.6,
C.sub.1-4alkoxyC.sub.1-4alkyl-, hydroxyC.sub.1-4alkyl-,
cycloalkylC.sub.0-4alkyl-, arylC.sub.0-4alkyl-, or
hetarylC.sub.0-4alkyl-, wherein any of the aryl or hetaryl rings
are optionally substituted with 1-2 independent halogen, cyano,
C.sub.1-4alkyl, C.sub.1-4alkoxy,
--N(C.sub.0-4alkyl)(C.sub.0-4alkyl), --SO.sub.2(C.sub.1-4alkyl,
--SO.sub.2N(C.sub.0-4alkyl)(C.sub.0-4alkyl), hydroxy, fluoromethyl,
difluoromethyl, or trifluoromethyl substituents;
[0025] R.sup.3 is hydrogen, --COOC.sub.0-4alkyl, C.sub.1-4alkoxy,
C.sub.1-4alkyl, arylC.sub.1-4alkylthio-, --C.sub.0-4alkylaryl,
--C.sub.0-4alkylhetaryl, --C.sub.0-4alkylcycloalkyl, or
--C.sub.0-4alkylheterocyclyl, wherein any of the rings is
optionally substituted with 1-3 independent halogen, cyano,
C.sub.1-4alkyl, fluoromethyl, difluoromethyl, trifluoromethyl,
--C.sub.0-4alkylNHC(O)O(C.sub.1-4alkyl),
--C.sub.0-4alkylNR.sup.7R.sup.8, --C(O)R.sup.9,
C.sub.1-4alkoxyC.sub.0-4alkyl-, --COOC.sub.0-4alkyl,
--C.sub.0-4alkylNHC(O)R.sup.9,
--C.sub.0-4alkylC(O)N(R.sup.10).sub.2,
--C.sub.1-4alkoxyC.sub.1-4alkoxy, hydroxyC.sub.0-4alkyl-,
--NHSO.sub.2R.sup.10, --SO.sub.2(C.sub.1-4alkyl),
--SO.sub.2NR.sup.11R.sup.12, 5- to 6-membered heterocyclyl,
phenylC.sub.0-2alkoxy, or phenylC.sub.0-2alkyl substituents,
wherein phenyl is optionally substituted with 1-2 independent
halogen, cyano, C.sub.1-4alkyl, C.sub.1-4alkoxy,
--N(C.sub.0-4alkyl)(C.sub.0-4alkyl), --SO.sub.2C.sub.1-4alkyl,
--SO.sub.2N(C.sub.0-4alkyl)(C.sub.0-4alkyl), hydroxy, fluoromethyl,
difluoromethyl, or trifluoromethyl substituents, or two bonds on a
ring carbon of the heterocyclyl group optionally can form an oxo
(.dbd.O) substituent;
[0026] or R.sup.3 is --NR.sup.4(--C.sub.0-4alkylR.sup.5);
[0027] R.sup.4 is C.sub.0-3alkyl, --C.sub.2-3alkyl-NR.sup.7R.sup.8,
C.sub.3-6cycloalkyl optionally substituted by
hydroxyC.sub.0-4alkyl- further optionally substituted by hydroxy,
C.sub.1-2alkoxyC.sub.2-4alkyl-, or
C.sub.1-2alkyl-S(O).sub.n--C.sub.2-3alkyl-;
[0028] n is 0, 1, or 2;
[0029] R.sup.5 is hydrogen, hydroxyC.sub.2-3alkyl-,
C.sub.1-2alkoxyC.sub.0-4alkyl-, or aryl, hetaryl, or
heterocyclyl;
[0030] wherein a heterocyclic nitrogen-containing R.sup.5 ring
optionally is mono-substituted on the ring nitrogen with
C.sub.1-4alkyl, benzyl, benzoyl, C.sub.1-4alkyl-C(O)--,
--SO.sub.2C.sub.1-4alkyl,
--SO.sub.2N(C.sub.0-4alkyl)(C.sub.0-4alkyl),
C.sub.1-4alkoxycarbonyl, or aryl(C.sub.1-4alkoxy)carbonyl; and
wherein the R.sup.5 rings are optionally mono-substituted on a ring
carbon with halogen, cyano, C.sub.1-4alkyl-C(O)--,
C.sub.1-4alkyl-SO.sub.2--, C.sub.1-4alkyl, C.sub.1-4alkoxy,
hydroxy, --N(C.sub.0-4alkyl)(C.sub.0-4alkyl),
hydroxyC.sub.0-4alkyl-, or C.sub.0-4alkylcarbamoyl-, provided that
no quaternised nitrogen is included; or two bonds on a ring carbon
of the heterocyclyl group optionally can form an oxo (.dbd.O)
substituent;
[0031] R.sup.6 is C.sub.1-4alkyl, aryl, or hetaryl;
[0032] R.sup.7 and R.sup.8 are independently C.sub.0-4alkyl,
C.sub.3-6cycloalkyl, or CO(C.sub.1-4alkyl);
[0033] R.sup.9 is C.sub.0-4alkyl, or C.sub.3-6cycloalkyl;
[0034] R.sup.10 is C.sub.0-4alkyl, or C.sub.3-6cycloalkyl; and
[0035] R.sup.11 and R.sup.12 are independently C.sub.0-4alkyl or
together with the nitrogen to which they are attached may form a 4-
to 6-membered heterocycle;
[0036] provided there are no nitrogen-oxygen, nitrogen-nitrogen,
oxygen-oxygen or nitrogen-halogen bonds in the grouping
--Y-Z-R.sup.3.
[0037] The molecular weight of the compounds of formula (I) is
preferably less than 800, more preferably less than 600.
[0038] X.sub.3 is preferably N.
[0039] Y is preferably --C(O)-- or --S(O).sub.2--.
[0040] Z is preferably a C.sub.1-4alkylene, oxygen,
--(CH.sub.2).sub.mO--, --NR-- or a bond. More preferably Z is a
bond.
[0041] R is preferably C.sub.0-4alkyl.
[0042] R.sup.1 and R.sup.1' are preferably each independently,
hydrogen, halogen or cyano. More preferably one of R.sup.1 and
R.sup.1' is hydrogen and the other is halogen, e.g. chloro. More
preferably one of R.sup.1 and R.sup.1' is hydrogen and the other is
5-chloro.
[0043] R.sup.2 is preferably C.sub.0-4alkyl. More preferably
R.sup.2 is hydrogen.
[0044] R.sup.3 is preferably hydrogen,
--NR.sup.4(--C.sub.0-4alkylR.sup.5), aryl, hetaryl, or heterocyclyl
wherein any of the rings is optionally substituted as described
above for formula (I).
[0045] R.sup.4 is preferably hydrogen.
[0046] Specific compounds of the invention which may be mentioned
are those included in the examples and pharmaceutically acceptable
salts thereof.
[0047] While the preferred groups for each variable have generally
been listed above separately for each variable, preferred compounds
of this invention include those in which several or each variable
in formula (I) is selected from the preferred, more preferred, most
preferred, especially or particularly listed groups for each
variable. Therefore, this invention is intended to include all
combinations of preferred, more preferred, most preferred,
especially and particularly listed groups.
[0048] As used herein, unless stated otherwise, "alkyl" as well as
other groups having the prefix "alk" such as, for example, alkoxy,
alkenyl, alkynyl, and the like, means carbon chains which may be
linear or branched or combinations thereof. Examples of alkyl
groups include methyl, ethyl, propyl, isopropyl, butyl, sec- and
tert-butyl, pentyl, hexyl, heptyl and the like. "Alkenyl",
"alkynyl" and other like terms include carbon chains having at
least one unsaturated carbon-carbon bond.
[0049] As used herein, for example, "C.sub.0-4alkyl" is used to
mean an alkyl having 0-4 carbons--that is, 0, 1, 2, 3, or 4 carbons
in a straight or branched configuration. An alkyl having no carbon
is hydrogen when the alkyl is a terminal group. An alkyl having no
carbon is a direct bond when the alkyl is a bridging (connecting)
group.
[0050] The term "cycloalkyl" means carbocycles containing no
heteroatoms, and include mono-, bi-, and tricyclic saturated
carbocycles, as well as fused and bridged systems. Such fused ring
systems can include one ring that is partially or fully
unsaturated, such as a benzene ring, to form fused ring systems,
such as benzofused carbocycles. Cycloalkyl includes such fused ring
systems as spirofused ring systems. Examples of cycloalkyl and
carbocyclic rings include C.sub.3-10cycloalkyl, e.g.
C.sub.3-8cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, and decahydronaphthalene, adamantane, indanyl,
1,2,3,4-tetrahydronaphthalene and the like.
[0051] The term "halogen" includes fluorine, chlorine, bromine, and
iodine atoms.
[0052] The term "aryl" is well known to chemists. The preferred
aryl groups are phenyl and naphthyl, especially phenyl.
[0053] The term "hetaryl" is well known to chemists. The term
includes 5- or 6-membered heteroaryl rings containing 1-4
heteroatoms chosen from oxygen, sulfur, and nitrogen in which
oxygen and sulfur are not next to each other. Examples of such
heteroaryl rings are furyl, thienyl, pyrrolyl, pyrazolyl,
imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl,
triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl,
pyridazinyl, pyrimidinyl, pyrazinyl, and triazinyl. The term
"hetaryl" includes hetaryl rings with fused carbocyclic ring
systems that are partially or fully unsaturated, such as a benzene
ring, to form a benzofused hetaryl. For example, benzimidazole,
benzoxazole, benzothiazole, benzofuran, quinoline, isoquinoline,
quinoxaline, and the like.
[0054] Unless otherwise stated, the terms "heterocyclic ring" and
"heterocyclyl" are equivalent, and include 4-8-membered saturated
or partially saturated rings containing one or two heteroatoms
chosen from oxygen, sulfur, and nitrogen. The sulfur and oxygen
heteroatoms are not directly attached to one another. Any nitrogen
heteroatoms in the ring may optionally be substituted with
C.sub.1-4alkyl. Examples of heterocyclic rings include azetidine,
oxetane, tetrahydrofuran, tetrahydropyran, oxepane, oxocane,
thietane, thiazolidine, oxazolidine, oxazetidine, pyrazolidine,
isoxazolidine, isothiazolidine, tetrahydrothiophene,
tetrahydrothiopyran, thiepane, thiocane, azetidine, pyrrolidine,
piperidine, N-methylpiperidine, azepane, azocane, [1,3]dioxane,
oxazolidine, piperazine, homopiperazine, morpholine,
thiomorpholine, 1,2,3,6-tetrahydropyridine and the like. Other
examples of heterocyclic rings include the oxidized forms of the
sulfur-containing rings. Thus, tetrahydrothiophene-1-oxide,
tetrahydrothiophene-1,1-dioxide, thiomorpholine-1-oxide,
thiomorpholine-1,1-dioxide, tetrahydrothiopyran-1-oxide,
tetrahydrothiopyran-1,1-dioxide, thiazolidine-1-oxide, and
thiazolidine-1,1-dioxide are also considered to be heterocyclic
rings. The term "heterocyclic" also includes fused ring systems and
can include a carbocyclic ring that is partially or fully
unsaturated, such as a benzene ring, to form benzofused
heterocycles. For example, 3,4-dihydro-1,4-benzodioxine,
tetrahydroquinoline, tetrahydroisoquinoline and the like.
[0055] Compounds described herein may contain one or more
asymmetric centers and may thus give rise to diastereomers and
optical isomers. The present invention includes all such possible
diastereomers as well as their racemic mixtures, their
substantially pure resolved enantiomers, all possible geometric
isomers, and pharmaceutically acceptable salts thereof. The above
formula (I) is shown without a definitive stereochemistry at
certain positions. The present invention includes all stereoisomers
of formula (I) and pharmaceutically acceptable salts thereof.
Further, mixtures of stereoisomers as well as isolated specific
stereoisomers are also included. During the course of the synthetic
procedures used to prepare such compounds, or in using racemization
or epimerization procedures known to those skilled in the art, the
products of such procedures can be a mixture of stereoisomers.
[0056] When a tautomer of the compound of formula (I) exists, the
present invention includes any possible tautomers and
pharmaceutically acceptable salts thereof, and mixtures thereof,
except where specifically drawn or stated otherwise.
[0057] When the compound of formula (I) and pharmaceutically
acceptable salts thereof exist in the form of solvates or
polymorphic forms, the present invention includes any possible
solvates and polymorphic forms. A type of a solvent that forms the
solvate is not particularly limited so long as the solvent is
pharmacologically acceptable. For example, water, ethanol,
propanol, acetone or the like can be used.
[0058] The term "pharmaceutically acceptable salts" refers to salts
prepared from pharmaceutically acceptable non-toxic bases or acids.
When the compound of the present invention is acidic, its
corresponding salt can be conveniently prepared from
pharmaceutically acceptable non-toxic bases, including inorganic
bases and organic bases. Salts derived from such inorganic bases
include aluminum, ammonium, calcium, copper (ic and ous), ferric,
ferrous, lithium, magnesium, potassium, sodium, zinc and the like
salts. Particularly preferred are the ammonium, calcium, magnesium,
potassium and sodium salts. Salts derived from pharmaceutically
acceptable organic non-toxic bases include salts of primary,
secondary, and tertiary amines, as well as cyclic amines and
substituted amines such as naturally occurring and synthesized
substituted amines. Other pharmaceutically acceptable organic
non-toxic bases from which salts can be formed include arginine,
betaine, caffeine, choline, N',N'-dibenzylethylenediamine,
diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol,
ethanolamine, ethylenediamine, N-ethylmorpholine,
N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine,
isopropylamine, lysine, methylglucamine, morpholine, piperazine,
piperidine, polyamine resins, procaine, purines, theobromine,
triethylamine, trimethylamine, tripropylamine, tromethamine and the
like.
[0059] When the compound of the present invention is basic, its
corresponding salt can be conveniently prepared from
pharmaceutically acceptable non-toxic acids, including inorganic
and organic acids. Such acids include, for example, acetic,
benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic,
fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic,
lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric,
pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric,
p-toluenesulfonic acid and the like
[0060] Since the compounds of formula (I) are intended for
pharmaceutical use they are preferably provided in substantially
pure form, for example at least 60% pure, more suitably at least
75% pure especially at least 98% pure (% are on a weight for weight
basis).
[0061] The compounds of formula (I) can be prepared as outlined in
Scheme 1 below wherein R.sup.1, R.sup.1', R.sup.2, R.sup.3,
X.sub.1, X.sub.2, X.sub.3, X.sub.4, Y and Z are as defined above
for formula (I):
##STR00004##
[0062] According to Scheme 1, the compounds of formula (I) may be
prepared by coupling the appropriate pyrrolopyridine-2-carboxylic
acid of formula (II) with the appropriate hydrazide of formula
(III), wherein Y.dbd.C(O). Compounds of formula (II) can be
obtained by the synthesis described in Scheme 7 below. Compounds of
formula (III) are generally commercially available or are readily
prepared by known techniques.
[0063] Typically, the compound of formula (II) is combined with
compounds of formula (III) in the presence of a suitable coupling
agent. Examples of suitable coupling reagents are
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide
hydrochloride/hydroxybenzotriazole (EDCI/HOBt),
1,1-carbonyldiimidazole (CDI),
dicyclohexylcarbodiimide/hydroxybenzotriazole (DCC 35/HOBt),
O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
tetrafluoroborate (R. Knorr et al., Tetrahedron Lett., 1989, 30,
1927-1930) and polymer supported
carbodiimide-1-hydroxybenzotriazole (for representative procedures,
see for example, Argonaut Technical Note 501 available from
Argonaut Technologies, Inc., Foster City, Calif.).
[0064] The couplings are performed in an inert solvent, preferably
an aprotic solvent at a temperature of about 0.degree. C. to about
45.degree. C. for about 1 to 72 h in the presence of a tertiary
amine base such as diisopropylethylamine (DIPEA) or triethylamine.
Exemplary solvents include acetonitrile, chloroform,
dichloromethane, N,N-dimethylformamide (DMF) or mixtures thereof.
Use of these coupling agents and appropriate selection of solvents
and temperatures are known to those skilled in the art or can be
readily determined from the literature. These and other exemplary
conditions useful for coupling carboxylic acids are described in
Houben-Weyl, Vol XV, part II, E. Wunsch, Ed., G. Thieme Verlag,
1974, Stuttgart, and M. Bodansky, Principles of Peptide Synthesis,
Springer-Verlag, Berlin, 1984 and The Peptides, Analysis, Synthesis
and Biology (Ed., E. Gross and J. Meienhofer), Vols 1-5, Academic
Press NY 1979-1983.
[0065] The compounds of formula (I), wherein Y is C(O), may also be
prepared according to Scheme 2 by coupling the appropriate
hydrazide of formula (IV) with the appropriate carboxylic acid of
formula (V). Examples of suitable coupling agents and conditions
are as described above. Compounds of formula (IV) can be obtained
by the synthesis described in Scheme 9 below. Compounds of formula
(V) are commercially available or are readily prepared by known
techniques.
##STR00005##
[0066] The compounds of formula (I), wherein Y is C(O) or
--SO.sub.2--, may be prepared according to Scheme 3 by mixing the
appropriate hydrazide of formula (IV) with the appropriate acid
chloride or sulfonyl chloride of formula (VI) in pyridine at room
temperature, or alternatively in the presence of a tertiary amine
base, e.g. diisopropylethylamine in a solvent such as 1,4-dioxane
or THF at room temperature. Acid chlorides or sulfonyl chlorides of
formula (VI) are commercially available or are readily prepared by
known techniques.
##STR00006##
[0067] The compounds of formula (I), wherein Y is C(O) and Z is NH,
may be prepared according to Scheme 4 by heating the appropriate
hydrazide of formula (IV) with the appropriate isocyanate of
formula (VII) under reflux in the presence of a tertiary amine
base, e.g. diisopropylethylamine in a solvent such as 1,4-dioxane
or toluene.
##STR00007##
[0068] The compounds of formula (I), wherein Y is C(O), and Z is
oxygen, may be prepared according to Scheme 5 by mixing the
appropriate hydrazide of formula (IV) with the appropriate
chloroformate of formula (VIII) in the presence of a tertiary amine
base, e.g. triethylamine in a solvent such as dichloromethane.
##STR00008##
[0069] The compounds of formula (I), wherein Y is C(NH), may be
prepared according to Scheme 6 by mixing the appropriate hydrazide
of formula (IV) with the appropriate thioimidate of formula (XV) in
a solvent such as ethanol or dimethylformamide.
##STR00009##
[0070] The compounds of formula (II) may be prepared according to
Scheme 7. Compounds of formula (X) may be prepared by condensation
of ortho-methyl nitro compounds of formula (IX) with an oxalate
ester in a solvent such as diethyl ether in the presence of a base
such as potassium ethoxide or DBU. Compounds of formula (XI) are
prepared from compounds of formula (X) under reducing conditions,
such as iron powder and ammonium chloride in ethanol at about
70.degree. C., or by hydrogenation in ethanol using palladium
catalysis at around 20.degree. C. Compounds of formula (XI) undergo
ester hydrolysis using aqueous alkali under standard conditions to
give pyrrolopyridine-2-carboxylic acids of formula (II).
##STR00010##
[0071] This three step process is similar to the Reissert indole
synthesis (Reissert, Chemische Berichte 1897, 30, 1030). Conditions
for accomplishing this sequence and references thereto, are
described in Kermack et al., J. Chem, Soc., 1921, 119, 1602; Cannon
et al., J. Med. Chem. 1981, 24, 238; and Julian et al., in
Heterocyclic compounds, Vol 3 (Wiley, New York, N.Y., 1962, R. C.
Elderfield, Ed. p 18).
[0072] Alternatively, the compounds of formula (XI) wherein X.sub.2
is nitrogen can be prepared as illustrated in Scheme 8.
##STR00011##
[0073] Deprotonation of compounds of formula (XVI) with an
organolithium such as n-butyllithium in a suitable solvent such as
THF, followed by quenching with methyl iodide gives compounds of
formula (XVII). Such compounds can undergo further deprotonation
with tert-butyllithium, in a suitable solvent such as THF, followed
by quenching with diethyl oxalate and subsequent heating of the
intermediate under reflux in hydrochloric acid, to give compounds
of formula (XI).
[0074] Further details for the preparation of compounds of formula
(II) can be found in WO04/104001 and the examples therein.
[0075] Formula (XIII) compounds may be prepared as described in
Scheme 9 by coupling of carboxylic acids of formula (II) with
hydrazines of formula (XII), wherein PG is a protecting group, e.g.
Boc. Examples of suitable coupling agents and conditions are as
described above for Scheme 1. Formula (IV) compounds may then be
prepared by removal of the protecting group, e.g. where PG is Boc,
under acidic conditions using for example trifluoroacetic acid in
dichloromethane at temperatures of around 25.degree. C. Formula
(II) compounds are made as described above (Scheme 7) or are
commercially available. Formula (XII) compounds are commercially
available or are readily prepared by known techniques.
[0076] Alternatively compounds of formula (IV), wherein R.sup.2 is
hydrogen, may be prepared (Scheme 9) by heating an ethyl ester of
formula (XI) with compounds of formula (XIV), wherein R.sup.2 is
hydrogen, in a solvent such as ethanol under reflux for a period of
3 to 24 h.
##STR00012##
[0077] Further details for the preparation of the compounds of
formula (I) are found in the examples.
[0078] The compounds of formula (I) may be prepared singly or as
compound libraries comprising at least 2, for example 5 to 1,000
compounds and more preferably 10 to 100 compounds of formula (I).
Compound libraries may be prepared by a combinatorial "split and
mix" approach or by multiple parallel synthesis using either
solution or solid phase chemistry, using procedures known to those
skilled in the art.
[0079] During the synthesis of the compounds of formula (I), labile
functional groups in the intermediate compounds, e.g. hydroxy,
carboxy and amino groups, may be protected. The compounds of
formulae (II) and (IV) may be protected in the 1-position e.g. with
an arylmethyl, acyl, alkoxycarbonyl, sulfonyl or silyl group. The
protecting groups may be removed at any stage in the synthesis of
the compounds of formula (I) or may be present on the final
compound of formula (I). A comprehensive discussion of the ways in
which various labile functional groups may be protected and methods
for cleaving the resulting protected derivatives is given in for
example, Protective Groups in Organic Chemistry, T. W. Greene and
P. G. M. Wuts, (1991) Wiley-Interscience, New York, 2.sup.nd
edition.
[0080] Any novel intermediates as defined above are also included
within the scope of the invention.
[0081] The invention also provides a compound of formula (IV):
##STR00013##
wherein R.sup.1, R.sup.1', R.sup.2, X.sub.1, X.sub.2, X.sub.3 and
X.sub.4 are as defined above for formula (I), or a protected
derivative thereof.
[0082] As indicated above the compounds of formula (I) are useful
as inhibitors of glycogen phosphorylase, for the treatment of
conditions such as diabetes, particularly Type II diabetes. For
such use the compounds of formula (I) will generally be
administered in the form of a pharmaceutical composition.
[0083] The invention also encompasses a pharmaceutical composition
comprising a compound of formula (I), or a pharmaceutically
acceptable salt thereof, in combination with a pharmaceutically
acceptable carrier.
[0084] Preferably the composition is comprised of a
pharmaceutically acceptable carrier and a non-toxic therapeutically
effective amount of a compound of formula (I), or a
pharmaceutically acceptable salt thereof.
[0085] Moreover, the invention also provides a pharmaceutical
composition for the treatment of disease by inhibiting glycogen
phosphorylase, resulting in the prophylactic or therapeutic
treatment of diabetes, hyperglycemia, hypercholesteroleinia,
hyperinsulinemia, hyperlipidemia, hypertension, atherosclerosis or
tissue ischemia, e.g. myocardial ischemia, cardioprotection or
inhibition of abnormal cell growth, comprising a pharmaceutically
acceptable carrier and a non-toxic therapeutically effective amount
of compound of formula (I), or a pharmaceutically acceptable salt
thereof.
[0086] The pharmaceutical compositions may optionally comprise
other therapeutic ingredients or adjuvants. The compositions
include compositions suitable for oral, rectal, topical, and
parenteral (including subcutaneous, intramuscular, and intravenous)
administration, although the most suitable route in any given case
will depend on the particular host, and nature and severity of the
conditions for which the active ingredient is being administered.
The pharmaceutical compositions may be conveniently presented in
unit dosage form and prepared by any of the methods well known in
the art of pharmacy.
[0087] In practice, the compounds of formula (I), or
pharmaceutically acceptable salts thereof, can be combined as the
active ingredient in intimate admixture with a pharmaceutical
carrier according to conventional pharmaceutical compounding
techniques. The carrier may take a wide variety of forms depending
on the form of preparation desired for administration, e.g. oral or
parenteral (including intravenous).
[0088] Thus, the pharmaceutical compositions can be presented as
discrete units suitable for oral administration such as capsules,
cachets or tablets each containing a predetermined amount of the
active ingredient. Further, the compositions can be presented as a
powder, as granules, as a solution, as a suspension in an aqueous
liquid, as a non-aqueous liquid, as an oil-in-water emulsion, or as
a water-in-oil liquid emulsion. In addition to the common dosage
forms set out above, the compound of formula (I), or a
pharmaceutically acceptable salt thereof, may also be administered
by controlled release means and/or delivery devices. The
compositions may be prepared by any of the methods of pharmacy. In
general, such methods include a step of bringing into association
the active ingredient with the carrier that constitutes one or more
necessary ingredients. In general, the compositions are prepared by
uniformly and intimately admixing the active ingredient with liquid
carriers or finely divided solid carriers or both. The product can
then be conveniently shaped into the desired presentation.
[0089] The compounds of formula (I), or pharmaceutically acceptable
salts thereof, can also be included in pharmaceutical compositions
in combination with one or more other therapeutically active
compounds.
[0090] The pharmaceutical carrier employed can be, for example, a
solid, liquid, or gas. Examples of solid carriers include lactose,
terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium
stearate, and stearic acid. Examples of liquid carriers are sugar
syrup, peanut oil, olive oil, and water. Examples of gaseous
carriers include carbon dioxide and nitrogen.
[0091] In preparing the compositions for oral dosage form, any
convenient pharmaceutical media may be employed. For example,
water, glycols, oils, alcohols, flavoring agents, preservatives,
coloring agents, and the like may be used to form oral liquid
preparations such as suspensions, elixirs and solutions; while
carriers such as starches, sugars, microcrystalline cellulose,
diluents, granulating agents, lubricants, binders, disintegrating
agents, and the like may be used to form oral solid preparations
such as powders, capsules and tablets. Because of their ease of
administration, tablets and capsules are the preferred oral dosage
units whereby solid pharmaceutical carriers are employed.
Optionally, tablets may be coated by standard aqueous or nonaqueous
techniques.
[0092] A tablet containing the composition of this invention may be
prepared by compression or molding, optionally with one or more
accessory ingredients or adjuvants. Compressed tablets may be
prepared by compressing, in a suitable machine, the active
ingredient in a free-flowing form such as powder or granules,
optionally mixed with a binder, lubricant, inert diluent, surface
active or dispersing agent. Moulded tablets may be made by moulding
in a suitable machine, a mixture of the powdered compound moistened
with an inert liquid diluent. Each tablet preferably contains from
about 0.05 mg to about 5 g of the active ingredient and each cachet
or capsule preferably containing from about 0.05 mg to about 5 g of
the active ingredient.
[0093] For example, a formulation intended for the oral
administration to humans may contain from about 0.5 mg to about 5 g
of active agent, compounded with an appropriate and convenient
amount of carrier material which may vary from about 5 to about 95
percent of the total composition. Unit dosage forms will generally
contain between from about 1 mg to about 2 g of the active
ingredient, typically 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg,
500 mg, 600 mg, 800 mg, or 1000 mg.
[0094] Pharmaceutical compositions of the present invention
suitable for parenteral administration may be prepared as solutions
or suspensions of the active compounds in water. A suitable
surfactant can be included such as, for example,
hydroxypropylcellulose. Dispersions can also be prepared in
glycerol, liquid polyethylene glycols, and mixtures thereof in
oils. Further, a preservative can be included to prevent the
detrimental growth of microorganisms.
[0095] Pharmaceutical compositions of the present invention
suitable for injectable use include sterile aqueous solutions or
dispersions. Furthermore, the compositions can be in the form of
sterile powders for the extemporaneous preparation of such sterile
injectable solutions or dispersions. In all cases, the final
injectable form must be sterile and must be effectively fluid for
easy syringability. The pharmaceutical compositions must be stable
under the conditions of manufacture and storage; thus, preferably
should be preserved against the contaminating action of
microorganisms such as bacteria and fungi. The carrier can be a
solvent or dispersion medium containing, for example, water,
ethanol, polyol (e.g. glycerol, propylene glycol and liquid
polyethylene glycol), vegetable oils, and suitable mixtures
thereof.
[0096] Pharmaceutical compositions of the present invention can be
in a form suitable for topical use such as, for example, an
aerosol, cream, ointment, lotion, dusting powder, or the like.
Further, the compositions can be in a form suitable for use in
transdermal devices. These formulations may be prepared, using a
compound of formula (I), or a pharmaceutically acceptable salt
thereof, via conventional processing methods. As an example, a
cream or ointment is prepared by admixing hydrophilic material and
water, together with about 5 wt % to about 10 wt % of the compound,
to produce a cream or ointment having a desired consistency.
[0097] Pharmaceutical compositions of this invention can be in a
form suitable for rectal administration wherein the carrier is a
solid. It is preferable that the mixture forms unit dose
suppositories. Suitable carriers include cocoa butter and other
materials commonly used in the art. The suppositories may be
conveniently formed by first admixing the composition with the
softened or melted carrier(s) followed by chilling and shaping in
molds.
[0098] In addition to the aforementioned carrier ingredients, the
pharmaceutical formulations described above may include, as
appropriate, one or more additional carrier ingredients such as
diluents, buffers, flavoring agents, binders, surface-active
agents, thickeners, lubricants, preservatives (including
anti-oxidants) and the like. Furthermore, other adjuvants can be
included to render the formulation isotonic with the blood of the
intended recipient. Compositions containing a compound of formula
(I), or pharmaceutically acceptable salts thereof, may also be
prepared in powder or liquid concentrate form.
[0099] Generally, dosage levels on the order of 0.01 mg/kg to about
150 mg/kg of body weight per day are useful in the treatment of the
above-indicated conditions, or alternatively about 0.5 mg to about
7 g per patient per day. For example, diabetes and hyperglycemia
may be effectively treated by the administration of from about 0.01
to 50 mg of the compound per kilogram of body weight per day, or
alternatively about 0.5 mg to about 3.5 g per patient per day.
Similarly, hypercholesterolemia, hyperinsulinemia, hyperlipidemia,
atherosclerosis or myocardial ischemia may be effectively treated,
or cardioprotection or inhibition of abnormal cell growth achieved,
by the administration of from about 0.01 to 50 mg of the compound
per kilogram of body weight per day, or alternatively about 0.5 mg
to about 3.5 g per patient per day.
[0100] It is understood, however, that the specific dose level for
any particular patient will depend upon a variety of factors
including the age, body weight, general health, sex, diet, time of
administration, route of administration, rate of excretion, drug
combination and the severity of the particular disease undergoing
therapy.
[0101] The compounds of formula (I) may be used in the treatment of
diseases or conditions in which glycogen phosphorylase plays a
role.
[0102] Thus the invention also provides a method for the treatment
of a disease or condition in which glycogen phosphorylase plays a
role comprising a step of administering to a subject in need
thereof an effective amount of a compound of formula (I), or a
pharmaceutically acceptable salt thereof.
[0103] Diseases or conditions in which glycogen phosphorylase plays
a role include diabetes (including Type I and Type II, impaired
glucose tolerance, insulin resistance and diabetic complications
such as neuropathy, nephropathy, retinopathy and cataracts),
hyperglycemia, hypercholesterolemia, hyperinsulinemia,
hyperlipidemia, hypertension, atherosclerosis, tissue ischemia e.g.
myocardial ischemia, cardioprotection and abnormal cell growth e.g.
cancer or hyperproliferative disorders.
[0104] The invention also provides a method for the treatment of
hyperglycemia or diabetes, particularly Type II diabetes,
comprising a step of administering to a subject in need thereof an
effective amount of a compound of formula (I), or a
pharmaceutically acceptable salt thereof.
[0105] The invention also provides a method for the prevention of
diabetes in a human demonstrating pre-diabetic hyperglycemia or
impaired glucose tolerance comprising a step of administering to a
subject in need thereof an effective prophylactic amount of a
compound of formula (I), or a pharmaceutically acceptable salt
thereof.
[0106] In the treatment of diabetes, e.g. Type II diabetes, the
compounds of the invention are particularly suited to night time
dosing, optionally in combination with another antidiabetic
agent.
[0107] The invention also provides a method for the treatment of
hypercholesterolemia, hyperinsulinemia, hyperlipidemia,
hypertension, atherosclerosis or tissue ischemia, or achieving
cardioprotection or inhibition of abnormal cell growth, comprising
a step of administering to a patient in need thereof an effective
amount of a compound of formula (I), or a pharmaceutically
acceptable salt thereof.
[0108] The invention also provides the use of a compound of formula
(I), or a pharmaceutically acceptable salt thereof, in the
treatment of a condition as defined above.
[0109] The invention also provides the use of a compound of formula
(I), or a pharmaceutically acceptable salt thereof, in the
manufacture of a medicament for the treatment of a condition as
defined above.
[0110] In the methods of the invention the term "treatment"
includes both therapeutic and prophylactic treatment.
[0111] The compounds of formula (I), or pharmaceutically acceptable
salts thereof, may be administered alone or in combination with one
or more other therapeutically active compounds. The other
therapeutically active compounds may be for the treatment of the
same disease or condition as the compounds of formula (I) or a
different disease or condition. The therapeutically active
compounds may be administered simultaneously, sequentially or
separately.
[0112] The compounds of Formula (I) may be administered with other
active compounds for the treatment of diabetes, for example insulin
and insulin analogs, sulfonyl ureas and analogs, biguanides,
.alpha.2 agonists, fatty acid oxidation inhibitors,
.alpha.-glucosidase inhibitors, .beta.-agonists, phosphodiesterase
inhibitors, lipid lowering agents, antiobesity agents, amylin
antagonists, lipoxygenase inhibitors, somostatin analogs,
glucokinase activators, glucagon antagonists, insulin signalling
agonists, PTP1B inhibitors, gluconeogenesis inhibitors,
antilypolitic agents, GSK inhibitors, galanin receptor agonists,
anorectic agents, CCK receptor agonists, leptin, CRF antagonists or
CRF binding proteins.
[0113] The compounds of formula (I) may also be administered in
combination with thyromimetic compounds, aldose reductase
inhibitors, glucocorticoid receptor antagonists, NHE-1 inhibitors
or sorbitol dehydrogenase inhibitors.
[0114] All publications, including, but not limited to, patents and
patent application cited in this specification, are herein
incorporated by reference as if each individual publication were
specifically and individually indicated to be incorporated by
reference herein as fully set forth.
[0115] The invention will now be described by reference to the
following examples which are for illustrative purposes and are not
to be construed as a limitation of the scope of the present
invention.
EXAMPLES
Materials & Methods
[0116] Column chromatography was carried out on SiO.sub.2 (40-63
mesh). LCMS data were obtained using a Waters Symmetry 3.5
.mu.C.sub.18 column (2.1.times.30.0 mm, flow rate=0.8 mL
min.sup.-1) eluting with a (5% MeCN in H.sub.2O)-MeCN solution
containing 0.1% HCO.sub.2H over 6 min & UV detection at 220 nm.
Gradient information: 0.0-1.2 min: 100% (5% MeCN in H.sub.2O);
1.2-3.8 min: Ramp up to 10% (5% MeCN in H.sub.2O)-90% MeCN; 3.8-4.4
min: Hold at 10% (5% MeCN in H.sub.2O)-90% MeCN; 4.4-5.5 min: Ramp
up to 100% MeCN; 5.5-6.0 min: Return to 100% (5% MeCN in H.sub.2O).
The mass spectra were obtained employing an electrospray ionisation
source in the positive (ES.sup.+) ion mode. Mass directed
purification was performed on a Micromass Platform LC with cone
voltage 30 v, employing an electrospray ionisation source in the
positive (ES.sup.+) ion mode, Waters 996 Photodiode Array Detector
(210-390 nm), Xterra Prep MS, C.sub.18, 5.mu. 19.times.50 mm
columns, and a mobile Phase of MeCN+0.1% Formic Acid/H.sub.20+5%
MeCN+0.1% Formic Acid. NMR spectra were acquired at 27.degree. C.
on a Varian Mercury 400 spectrometer operating at 400 MHz or on a
Bruker AMX2 500 spectrometer operating at 500 MHz.
Abbreviations & Acronyms:
[0117] CDI: 1,1-carbonyldiimidazole; DIPEA:
N,N-Diisopropylethylamine; DMF: N,N-Dimethylformamide; DMSO:
Dimethylsulfoxide; EDCI:
1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride; GP:
Glycogen Phosphorylase; Glc: Glucose; G6P: Glucose-6-phosphate;
G6PDH: Glucose-6-phosphate dehydrogenase; HATU:
O-(7-Azabenzotriazol-1-yl)-N,N,N', N'-tetramethyluronium
hexafluorophosphate; HOBt: 1-Hydroxybenzotriazole; PS: Polymer
supported; rt: room temperature; RT: Retention time; THF:
Tetrahydrofuran.
Intermediates:
Preparation 1
6-Methyl-5-nitro-1H-pyridin-2-one
##STR00014##
[0119] The title compound was prepared according to the method of
Baumgarten and Su., (J. Am. Chem. Soc., 1952, 74, 3828).
.delta..sub.H (d.sub.6 DMSO): 2.62 (3H, s), 6.28 (1H, d), 8.10 (1H,
d).
Preparation 2
2-Chloro-6-methyl-4-nitropyridine
##STR00015##
[0121] A suspension of 6-methyl-5-nitro-1H-pyridin-2-one
(Preparation 1, 3.53 g, 22.9 mmol) in phosphorous oxychloride (20
mL) was heated to 115.degree. C. for 3 h then allowed to cool to
rt. The phosphorous oxychloride was removed in vacuo and the
residue poured into iced water (100 mL). The mixture was quenched
by addition of saturated sodium bicarbonate solution then the
aqueous mixture was extracted with ethyl acetate (3.times.100 mL).
The combined organics were washed with brine, dried (MgSO.sub.4),
filtered and concentrated in vacuo to give the title compound.
.delta..sub.H (CDCl.sub.3): 2.86 (3H, s), 7.36 (1H, d), 8.27 (1H,
d).
Preparation 3
3-(2-Chloro-5-nitropyridin-6-yl)-2-oxopropionic acid ethyl
ester
##STR00016##
[0123] To a solution of potassium ethoxide (134 mg, 1.59 mmol) in
diethyl ether (5 mL) and ethanol (1 mL) was added diethyl oxalate
(218 .mu.L, 1.59 mmol) in one portion and the resulting solution
was stirred for 30 min at rt. 2-Chloro-6-methyl-5-nitropyridine
(Preparation 2, 250 mg, 1.45 mmol) was added as a suspension in
diethyl ether (2 mL) and stirring was continued for 17 h at rt. The
mixture was filtered on a sinter, washing with cold diethyl ether.
The collected precipitate was dissolved in glacial acetic acid then
evaporated to dryness in vacuo to give the title compound.
.delta..sub.H (CDCl.sub.3): 1.40 (3H, t), 4.38 (2H, q), 7.33 (1H,
d), 7.37 (1H, s), 8.40 (1H, d).
Preparation 4
5-Chloro-1H-pyrrolo[3,2-b]pyridine-2-carboxylic acid ethyl
ester
##STR00017##
[0125] To a solution of
3-(2-chloro-5-nitropyridin-6-yl)-2-oxopropionic acid ethyl ester
(Preparation 3, 1.53 g, 5.6 mmol) in THF (65 mL) and ethanol (30
mL) was added saturated aqueous ammonium chloride solution (30 mL)
and the suspension was vigorously stirred at rt. Iron powder (1.95
g, 34.8 mmol) was added portionwise and the mixture was heated
under reflux for 2 h then allowed to cool prior to filtration
through a celite plug, and washed with warm THF. The mixture was
concentrated under reduced pressure to give an aqueous suspension,
which was filtered through a sinter, washing with water. The wet
solid was washed with methanol and dried. The residue was adsorbed
onto silica gel and purified via flash chromatography eluting with
ethyl acetate/hexane (1:19) to give the title compound.
.delta..sub.H (CD.sub.3OD): 1.42 (3H, t), 4.42 (2H, q), 7.15 (1H,
s), 7.30 (1H, d), 7.89 (1H, d); m/z (ES.sup.+)=225.03 [M+H].sup.+,
RT=3.32 min.
Preparation 5
5-Chloro-1H-pyrrolo[3,2-b]pyridine-2-carboxylic acid
##STR00018##
[0127] To a stirred solution of
5-chloro-1H-pyrrolo[3,2-b]pyridine-2-carboxylic acid ethyl ester
(Preparation 4, 151 mg, 0.67 mmol) in ethanol (10 mL) was added
sodium hydroxide (0.35 mL, 2M) and the stirred solution was heated
to 70.degree. C. for 2 h. The reaction mixture was allowed to cool
to rt and left to stand for 16 h. The pH was adjusted to 4 by
addition of glacial acetic acid, the solvents removed in vacuo to
give a white solid, which was suspended in dichloromethane and
filtered through a sinter, washing with additional dichloromethane.
The filter cake was then washed with ethyl acetate (3.times.30 mL)
and dried to give the title compound. .delta..sub.H (CD.sub.3OD):
6.97 (1H, s), 7.17 (1H, d), 7.83 (1H, d); m/z (ES.sup.+)=197
[M+H].sup.+; RT=2.82 min.
Preparation 6
3-(2-Chloro-5-nitropyridin-4-yl)-2-oxopropionic acid ethyl
ester
##STR00019##
[0129] To a solution of potassium ethoxide (1.46 g, 17.4 mmol) in
diethyl ether (80 mL) and ethanol (10 mL) under an argon atmosphere
was added diethyl oxalate (2.4 mL, 17.4 mmol) and the mixture was
stirred at rt for 30 min. A solution of
2-chloro-4-methyl-5-nitropyridine (3.0 g, 17.4 mmol) in diethyl
ether (20 mL) was added resulting in the formation of a dark green
precipitate. The reaction was stirred at rt for 15 h, cooled to
0.degree. C., filtered and washed with cold diethyl ether to give a
dark green solid. The solid was dissolved in water (200 mL) and
acidified to pH 4 with acetic acid to give a precipitate. The solid
was collected by filtration and dried to give the title compound.
m/z (ES.sup.+)=273 [M+H].sup.+.
Preparation 7
5-Chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid ethyl
ester
##STR00020##
[0131] 3-(2-Chloro-5-nitropyridin-4-yl)-2-oxopropionic acid ethyl
ester (Preparation 6, 3.0 g, 11.0 mmol) was dissolved in ethanol
(100 mL) and THF (50 mL). Iron powder (3.7 g, 66.0 mmol) and
saturated ammonium chloride solution (50 mL) were added and the
mixture was heated under reflux for 2 h. The mixture was cooled,
filtered through celite and washed several times with ethyl
acetate. The organic layers were combined, washed with brine (100
mL), dried (MgSO.sub.4) and concentrated in vacuo to give the title
compound. .delta..sub.H (CD.sub.3OD): 1.42 (3H, t), 4.44 (2H, q),
7.15 (1H, s), 7.70 (1H, s), 8.59 (1H, s); m/z (ES.sup.+)=225
[M+H].sup.+.
Preparation 8
5-Chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid
##STR00021##
[0133] To a solution of
5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid ethyl ester
(Preparation 7, 1.78 g, 7.9 mmol) in ethanol (70 mL) was added
sodium hydroxide solution (5.2 mL, 2M, 10.3 mmol) and the mixture
was heated under reflux for 2 h. The solvent was removed in vacuo
and the solid dissolved in water (150 mL) and acidified to pH 4
with acetic acid to give the title compound as a solid that was
isolated by filtration. .delta..sub.H (CD.sub.3OD): 7.13 (1H, s),
7.68 (1H, s), 8.58 (1H, s); m/z (ES.sup.+)=197 [M+H].sup.+.
Preparation 9
Tetrahydropyran-4-carboxylic acid
##STR00022##
[0135] This compound was prepared by hydrolysis of the methyl ester
according to the method of Spiegler and Goetz, Ger. Offen. (1987)
DE 3536956 A1.
Preparation 10
5-Chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid hydrazide
##STR00023##
[0136] Route 1
[0137]
N'-(tert-Butyloxycarbonyl)-5-chloro-1H-pyrrolo[2,3-c]pyridine-2-car-
boxylic acid hydrazide (EXAMPLE 25, 930 mg, 2.99 mmol) was
suspended in a mixture of dichloromethane and trifluoroacetic acid
(1:1, 20 mL). After 2 h the mixture was concentrated in vacuo and
the oily residue was dissolved in water (200 mL). The aqueous layer
was washed with ethyl acetate (2.times.50 mL) and concentrated in
vacuo to give the title compound as its trifluoroacetic acid salt.
.delta..sub.H (d.sub.6 DMSO) 7.36 (1H, s), 7.83 (1H, s), 8.66 (1H,
s), 9.3-10.8 (3H, br s), 11.8-12.2 (1H, br s), 12.6 (1H, s); m/z
(ES.sup.+)=211 [M+H].sup.+; RT=0.42 min.
Route 2
[0138] To a solution of
5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid ethyl ester
(Preparation 7, 880 mg, 3.91 mmol) in ethanol (30 mL) was added
hydrazine monohydrate (4.0 mL, 78.22 mmol). The resulting solution
was refluxed at 90.degree. C. for 5 h. The reaction mixture was
cooled to rt and the precipitate was filtered and dried to give the
title compound. m/z (ES.sup.+) 211 [M+H].sup.+; RT=1.65 min.
Example 1
5-Chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid
N'-(thiophene-2-yl-aminocarbonyl) hydrazide
##STR00024##
[0140] DIPEA (53 .mu.L, 0.31 mmol) and thienyl isocyanate (40
.mu.L, 0.32 mmol) were added to a suspension of
5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid hydrazide
trifluoroacetic acid salt (Preparation 10--route 1, 101 mg, 0.31
mmol) in a mixture of toluene and 1,4-dioxane (10 mL, 1:1). After
stirring the mixture at 100.degree. C. for 12 h, the reaction was
allowed to cool to rt and the solvent was removed. The remaining
oily residue was purified by flash chromatography on silica gel
(toluene/acetone:2/1) to give the title compound. .delta..sub.H
(CDCl.sub.3): 6.60 (1H, d), 6.78 (1H, m), 6.84 (1H, d), 7.26 (1H,
d), 7.82 (1H, s), 8.61 (2H, m), 9.97 (1H, s); m/z (ES.sup.+)=336
[M+H].sup.+; RT=2.97 min.
Example 2
Thiophene-3-carboxylic acid
N'-(5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carbonyl)hydrazide
##STR00025##
[0142] To a solution of
5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid hydrazide
trifluoroacetic acid salt (Preparation 10--route 1, 0.110 g, 0.34
mmol) in DMF (3 mL) was added DIPEA (170.0 .mu.L, 1.02 mmol). To
the stirred solution, HOBt (0.046 g, 0.34 mmol), EDCI (0.078 g,
0.41 mmol), DIPEA (120.0 .mu.L, 0.68 mmol) and
thiophene-3-carboxylic acid (0.044 g, 0.34 mmol) were added. The
reaction mixture was stirred at rt for 16 h and then concentrated
in vacuo to give an oil. On addition of ethyl acetate to the oil, a
solid precipitated. The solid was filtered and dried to give the
title compound. m/z (ES.sup.+)=321 [M+H].sup.+; RT=2.84 min.
[0143] The coupling of the appropriate carboxylic acid with
5-chloro-1H-pyrrolo[2,3-c]-pyridine-2-carboxylic acid hydrazide,
outlined in EXAMPLE 2, was also employed to prepare the compounds
listed in Table 1 below.
TABLE-US-00001 TABLE 1 EX. Structure Name RT m/z (ES.sup.+) 3
##STR00026## Furan-3-carboxylic
acidN'-(5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carbonyl)hydrazide
2.75 305 4 ##STR00027## Tetrahydrofuran-3- carboxylic acid
N'-(5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carbonyl)hydrazide 2.59
309 5 ##STR00028## 1H-Pyrrole-2-carboxylicacid
N'-(5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carbonyl)hydrazide 2.77
304 6 ##STR00029## Benzoic acid
N'-(5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carbonyl)hydrazide 3.02
315
Example 7
Benzo[1,3]dioxole-5-carboxylic acid
N'-(5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carbonyl)hydrazide
##STR00030##
[0145] To a solution of
5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid hydrazide
(Preparation 10--route 2, 0.100 g, 0.48 mmol) in DMF (4 mL) was
added HOBt (0.064 g, 0.48 mmol), EDCI (0.110 g, 0.58 mmol), DIPEA
(200 .mu.L, 0.96 mmol) and piperonylic acid (0.079 g, 0.48 mmol).
The reaction mixture was stirred at rt for 16 h. The reaction
mixture was poured into water (75 mL) and extracted with ethyl
acetate (2.times.150 mL). The combined organic extract was washed
with saturated sodium chloride (75 mL), dried (MgSO.sub.4) and
concentrated in vacuo to give a solid. The solid obtained was
purified by recrystallisation from methanol to give the title
compound. m/z (ES.sup.+)=359 [M+H].sup.+; RT=2.92 min.
[0146] The coupling of the appropriate carboxylic acid with
5-chloro-1H-pyrrolo[2,3-c]-pyridine-2-carboxylic acid hydrazide,
outlined above in EXAMPLE 7 was also employed to prepare the
compounds listed in Table 2 below.
TABLE-US-00002 TABLE 2 EX. Structure Name RT m/z (ES.sup.+) 8
##STR00031## Tetrahydropyran-4-carboxylic acid
N'-(5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carbonyl)hydrazide 2.49
323 9 ##STR00032## Cyclopropane carboxylicacid
N'-(5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carbonyl)hydrazide 2.42
279 10 ##STR00033## 4-Methylbenzoic acid
N'-(5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carbonyl)hydrazide 2.95
329 11 ##STR00034##
2(S)-[N'-5-Chloro-1H-pyrrolo[2,3-c]pyridine-2-carbonyl)-hydrazinocarbonyl-
]pyrrolidine-1-carboxylicacid tert-butyl ester 3.01 408 12
##STR00035## Pyrrolidine-2(S)-carboxylicacid
N'-(5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carbonyl)hydrazide 0.65
308 13 ##STR00036##
3(S)-N'-(5-Chloro-1H-pyrrolo[2,3-c]pyridine-2-carbonyl)-hydrazinocarbonyl-
]pyrrolidine-1-carboxylicacid tert-butyl ester 3.32 408 14
##STR00037## Pyrrolidine-3(S)-carboxylicacid
N'-(5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carbonyl)hydrazide 2.27
308
Example 15
Pyridine-3-carboxylic acid
N'-(5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carbonyl)hydrazide
##STR00038##
[0148] To a solution of nicotinic acid hydrazide (35 mg, 0.25 mmol)
in DMF (5 mL) was added triethylamine (88 .mu.L, 0.64 mmol),
5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (Preparation
8, 50 mg, 0.25 mmol), HOBt (34 mg, 0.25 mmol) and EDCI (50 mg, 0.28
mmol). The mixture was allowed to stir at rt for 16 h. The solvent
was removed in vacuo and the residue was partitioned between water
(100 mL) and ethyl acetate (100 mL). The organic layer was dried
(MgSO.sub.4) and concentrated in vacuo to give an oil, which was
purified by flash chromatography on silica gel
(dichloromethane/methanol, 9/1) to give the title compound. m/z
(ES.sup.+)=316 [M+H].sup.+; RT=2.62 min.
Example 16
5-Chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid
N'-phenylacetylhydrazide
##STR00039##
[0150] To a solution of
5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (Preparation
8, 50 mg, 0.25 mmol) in DMF (10 mL) was added DIPEA (89 .mu.L, 0.51
mmol), HOBt (34 mg, 0.25 mmol), EDCI (63 mg, 0.33 mmol) and
phenylacetic acid hydrazide (38 mg, 0.25 mmol) and the mixture was
stirred at rt for 72 h. The reaction mixture was partitioned
between water (50 mL) and ethyl acetate (3.times.30 mL). The
combined organics were washed with brine (20 mL), dried
(MgSO.sub.4) and concentrated in vacuo. The crude material was
chromatographed on silica gel eluting with methanol/dichloromethane
(1:19) to give the title compound. m/z (ES.sup.+)=329 [M+H].sup.+;
RT=3.07 min.
[0151] The coupling of the appropriate hydrazide with
5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid, outlined in
EXAMPLE 16, was also employed to prepare the compounds listed in
Table 3 below.
TABLE-US-00003 TABLE 3 EX. Structure Name RT (min) m/z (ES.sup.+)
17 ##STR00040## 5-Chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic
acidN'-(4-chlorophenylaminocarbonyl)hydrazide 3.30 364 18
##STR00041## 3,4-Dichlorobenzoic
acidN'-(5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carbonyl)hydrazide
3.40 385 19 ##STR00042## 2,3-Dihydro-benzo[1,4]dioxine-2-carboxylic
acid N'-(5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carbonyl)hydrazide
2.95 329 20 ##STR00043## 2-Chlorophenoxy acetyl
N'-(5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carbonyl)hydrazide 3.30
379 21 ##STR00044## Thiophene-2-carboxylic
acidN'-(5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carbonyl)hydrazide
2.95 321 22 ##STR00045## Furan-2-carboxylic acid
N'-(5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carbonyl)hydrazide 2.88
305 23 ##STR00046## 1-Methyl-1H-pyrrole-2-carboxylic acid
N'-(5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carbonyl)hydrazide 3.05
318
Example 24
3,4-Dichlorobenzoic acid
N'-(5-chloro-1H-pyrrolo[3,2-b]pyridine-2-carbonyl)hydrazide
##STR00047##
[0153] To a solution of
5-chloro-1H-pyrrolo[3,2-b]pyridine-2-carboxylic acid (Preparation
5, 20.0 mg, 0.10 mmol) in DMF (5 mL) was added 3,4-dichlorobenzoic
acid hydrazide (23 mg, 0.11 mmol), DIPEA (19.5 .mu.L, 0.11 mmol)
and HOBt (14.0 mg, 0.10 mmol). The resulting solution was stirred
for 5 min prior to the addition of EDCI (23 mg, 1.20 mmol). The
reaction mixture was stirred for 16 hr at rt then partitioned
between water (10 mL) and dichloromethane (20 mL) on a hydrophobic
frit. The aqueous phase was extracted with a further portion of
dichloromethane (30 mL) and the combined organics were concentrated
in vacuo. Trituration of the resulting residue with ethyl
acetate/dichloromethane gave the title compound. .delta..sub.H
(d.sub.6 DMSO): 12.25 (1H, s), 10.83 (2H, d), 8.17 (1H, s),
7.55-7.97 (3H, m), 7.38 (1H, s), 7.26 (1H, d); m/z (ES.sup.+)=383
[M+H].sup.+; RT=3.37 min.
Example 25
5-Chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid
N'-(tertbutyloxycarbonyl)hydrazide
##STR00048##
[0155] To a solution of
5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (Preparation
8, 2.05 g, 10.4 mmol) in DMF (30 mL), tert-butyl carbazate (1.38 g,
10.4 mmol), DIPEA (3.5 mL, 20.4 mmol), HOBt (1.58 g, 10.3 mmol) and
EDCI (2.54 g, 13.3 mmol) were added successively. The resulting
solution was stirred for 12 h at rt before adding water and brine
(1:1, 200 mL). The solution was extracted with ethyl acetate
(4.times.50 mL) and the combined organic layers were washed with
dilute hydrochloric acid (1N, 50 mL), dilute sodium hydroxide
solution (1N, 50 mL) and brine. The organic layer was dried
(MgSO.sub.4) and concentrated in vacuo to give a solid residue,
which was purified by flash chromatography on silica gel
(hexane/ethyl acetate, 1:3) to give the title compound.
.delta..sub.H (CDCl.sub.3): 1.42 (9H, s), 7.19 (1H, s), 7.78 (1H,
s), 8.60 (1H, s), 9.28 (1H, br s).
[0156] The biological activity of the compounds of the invention
may be tested in the following assay systems:
In Vitro GP Activity
Materials:
[0157] .alpha.-D-Glucose-1-Phosphate (disodium salt), Glycogen,
D-Glucose, Malachite Green Hydrochloride, Ammonium Molybdate
tetrahydrate, BSA, HEPES and rabbit muscle phosphorylase .alpha.
(P1261) were purchased from Sigma. All other reagents were
analytical grade.
Method
Glycogen Phosphorylase Assay In Vitro:
[0158] An assay for glycogen phosphorylase activity in the reverse
direction was developed based on the method described by Engers et
al., Can. J. Biochem., 1970, 48, 746-754]. Rabbit muscle glycogen
phosphorylase .alpha. (Sigma) was reconstituted at a stock
concentration of 100 .mu.g/mL in 25 mM Tris/HCl. The pH was
measured in a 96-well plate in a final volume of 100 .mu.L
containing 50 mM Hepes pH 7.2, 7.5 mM glucose, 0.5 mM
glucose-1-phosphate and 1 mg/mL glycogen. After incubation at
30.degree. C. for 30 min, the inorganic phosphate released from
glucose-1-phosphate was measured by the addition of 150 .mu.L of
malachite green/molybdate solution prepared as follows: 5 mL of
4.2% ammonium molybdate in 4N HCl, 5 mL of 0.045% malachite green,
50 .mu.L of Tween 20. Following a 30 min incubation at rt, the
absorbance was measured at 620 nm. For IC.sub.50 determination, 10
.mu.L of a serial dilution of compound (100M to 0.004 .mu.M) in
DMSO was added to each reaction in duplicate with the equivalent
concentration of DMSO added to the control uninhibited reaction.
Dose response curves were then obtained by plotting % inhibition
versus log.sub.10 compound concentration. IC.sub.50 is defined as
the concentration of compound achieving 50% inhibition under the
assay conditions described.
[0159] Examples of compounds of the present invention demonstrated
efficacy in the above assay with IC.sub.50 results in the range of
better than 100 .mu.M.
* * * * *